Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study.

Leukemia, Myelodysplasia, and Transplantation
Session Type and Session Title: 
Oral Abstract Session, Leukemia, Myelodysplasia, and Transplantation
Abstract Number: 


J Clin Oncol 33, 2015 (suppl; abstr LBA7005)
Asher Alban Akmal Chanan-Khan, Paula Cramer, Fatih Demirkan, Graeme Fraser, Rodrigo Santucci Silva, Halyna Pylypenko, Sebastian Grosicki, Ann Janssens, Alexander Pristupa, Jiri Mayer, Marie-Sarah Dilhuydy, Javier Loscertales, Nancy L. Bartlett, Abraham Avigdor, Simon Rule, Steven Sun, Michelle Mahler, Mariya Salman, Angela J. Howes, Michael J. Hallek; Mayo Clinic, Jacksonville, FL; University of Cologne, Cologne, Germany; Dokuz Eylul University, Department of Hematology, Izmir, Turkey, Izmir, Turkey; McMaster University, Hamilton, ON, Canada; IEP São Lucas / Hemomed Oncologia e Hematologia, Sao Paolo, Brazil; Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine; Department of Cancer Prevention, Faculty of Public Health, Silesian Medical University, Katowice, Poland; Universitaire Ziekenhuizen Leuven, Leuven, Belgium; Ryazan Regional Clinical Hospital, Ryazan, Russia; Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic; Hopital Haut Leveque, Bordeaux, France; Hematology Dept, Hospital Universitario La Princesa, Madrid, Spain; Washington University, Siteman Cancer Center, St Louis, MO; Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer and Sackler School of Medicine,University of Tel-Aviv, Tel-Aviv, Israel; Department of Hematology, Derriford Hospital, Plymouth, United Kingdom; Janssen Research & Development, Raritan, NJ; Janssen Research and Development, Raritan, NJ; Janssen Research and Development, High Wycombe, United Kingdom; Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital Cologne, Cologne, Germany

Abstract Disclosures


Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.